I-35 is named the Pan Am Expressway in San Antonio. There, it has brief concurrencies with I-10 (with it US 87) and I-410, and it serves as the northern terminus of I-37. I-35 heads northeast out of the city towards the state capital, Austin.

In Austin, I-35 is the Interregional Highway[5] and has a concurrency with US 290 through Downtown Austin. Throughout Austin, elevated express lanes were constructed on either side of the original freeway. Prior to this expansion, this section included an at-grade railroad crossing, which is extremely unusual for a freeway. From Austin, I-35 goes through Round Rock, Temple, Pflugerville, and Waco. In Belton, south of Temple, it serves as the current eastern terminus for I-14. In Waco, I-35 is known as the Jack Kultgen Freeway, and begins its concurrency with US 77. The campuses of both the University of Texas at Austin and Baylor University are located adjacent to I-35.

I-35 then heads to Hillsboro, where it splits into I-35W and I-35E and runs through the Dallas–Fort Worth area. The official mile markers, along with the route of US 77, follow I-35E through Dallas—I-35W, which is 85 miles (137 km) in length, carries its own mileage from Hillsboro to Denton, as though it were an x35 loop. In Dallas, I-35E is the R.L. Thornton Freeway south of I-30, which picks up the name heading east. North of I-30, it is the Stemmons Freeway.

After passing through Dallas and Fort Worth, I-35's two forks branches in Denton near the University of North Texas campus. The unified Interstate then continues north to Gainesville before crossing the Red River into Oklahoma.

Of note on the route, at several points between Cassoday and Emporia in the Flint Hills dirt driveways that provide direct access without a ramp, for cattle trucks, may be found in either direction along the highway.

BETO Junction is a highway intersection in Coffey County, Kansas that is the intersection of U.S. Highway 75 and I-35. It derives its name from the four major cities nearest the intersection: Burlington, Emporia, Topeka, and Ottawa. It is located 16 miles (26 km) north of Burlington at exit 155. Historically, the intersection referred to as "BETO Junction" before I-35 was constructed was located on the old US 75 highway alignments 2 miles (3.2 km) south and 2 miles (3.2 km) east, near Waverly, Kansas.

I-35 enters Missouri two miles (3 km) southwest of Kansas City's Central Business District as a six-lane highway. After merging with Southwest Trafficway and Broadway, it becomes eight lanes and continues north to downtown Kansas City, where it serves as the west and north legs of the downtown freeway loop. Along the north edge of the loop, I-35 joins with I-70 immediately west of Broadway and carries six lanes of traffic with a speed limit of 45 mph (72 km/h). Upon leaving the loop, Interstate 29 begins, concurrent with I-35. The two interstates cross the Missouri River together on the Bond Bridge.

After crossing the river, I-29 and I-35 split. I-35 heads north to Cameron, Missouri, and then continues northward to the Iowa state line.

In the southern sections of the state, I-35 is parallel to U.S. Route 69 for much of its course.

In Des Moines, I-35 has a 12-mile (19 km) overlap with I-80. The concurrency takes place northwest of the downtown district of the city. At exit 127 of I-80, the overlap turns east and terminates at exit 137 via an interchange with Interstate 235.

North of Des Moines, I-35 is mainly parallel with US 69, traversing a vast and rural area of Iowa.[6]

All of I-35 in the state of Minnesota from the Iowa state line to the city of Duluth is officially designated the Red Bull Highway, after the 34th Infantry (Red Bull) Division.

At Medford, Minnesota, the on/off ramps lead to roundabouts rather than standard cross intersections.[7] This is the first site in the state linked to a major highway to use roundabouts.

I-35 splits again into I-35W and I-35E in the Minneapolis/Saint Paul, Minnesota area. The mile- and exit-numbering sequence continues along I-35E. At one sharp turn in I-35W near the junction with I-94, drivers are advised to slow to 35 mph (55 km/h) (although many drivers are able to maintain the speed limit of 55 mph (90 km/h)). Additionally, it is not possible to go from westbound I-94 to northbound I-35W, from southbound I-35W to eastbound I-94, and vice versa, without resorting to surface streets.

On I-35E in Minnesota between Minnesota Highway 5 and Interstate 94, in both directions, trucks weighing more than 9,000 lbs (4,082 kg) are banned from the freeway, and the speed limit drops to 45 mph (70 km/h) but is rarely obeyed. This section was not completed until the late 1980s (although the route was cleared and graded earlier) due to opposition from the historic Crocus Hill neighborhood, which sits only a few hundred feet from the alignment. The four-lane alignment, "parkway" design was a compromise. The truck bypass for this section is signed on I-494 and I-694 to the east of Saint Paul.

The national northern terminus of I-35 is at an intersection in eastern Duluth. Drivers' options include merging with London Road/Minnesota Highway 61 northbound, proceeding through the stop lights onto 26th Avenue East, or turning left onto London Road southbound.

Some portions of I-35 in Oklahoma City were already built in 1953, before the Interstate system was created.[9] Through Norman, Oklahoma, the interstate opened in June 1959. In Moore, it opened in two parts: the northern half, connecting Moore to Oklahoma City, opened in January 1960. The southern half, linking it to Norman, was opened to traffic in June 1967.[10]

I-35 through Oklahoma largely parallels U.S. Route 77. This is in large part due to efforts of the towns of Wynnewood, Paoli, and Wayne, which fought to keep I-35 as close as possible to U.S. 77. This was successful due to a threat from Governor Henry Bellmon to build a toll road rather than I-35, and legislation preventing state funds for the interstate from being spent if it were more than 1-mile (1.6 km) from the U.S. route.[11]

I-35 was completed in Oklahoma in 1971, when parts of the interstate running through Carter Co. and Murray Co. were opened to traffic.[9]

The final segment of I-35 (as originally planned) to open was in north central Iowa, between Mason City and US 20 near Iowa Falls. This segment was delayed due to some controversy. Originally, I-35 was to follow the alignment of US 69 from Des Moines all the way to the Minnesota border. However, Mason City's business community lobbied for the route to be moved closer to their city. On September 1, 1965, the alignment was changed to instead parallel US 65 through northern Iowa, which brought the highway much closer to Mason City. This, however, created a long diagonal section through Wright and Franklin counties. Local farmers objected to their farms being bisected into triangular pieces, and resulting litigation delayed I-35 for several years. A November 1972 ruling rejected a lawsuit filed by the farmers, and the final segment of I-35 was allowed to proceed, eventually opening in 1975. One of the final pieces of the highway puzzle happened in Faribault, Minnesota. For approximately 25 years, Highway 35 actually went through the town and travelers had to deal with several traffic lights. In 1975, the highway went around Faribault where today a traveler actually has three exit choices for this southern Minnesota town.

The proposed Trans-Texas Corridor toll-road project included one proposal (TTC-35) to primarily parallel I-35 from the Mexican border up to the Oklahoma border.[13] There are major disagreements as to what impact this parallel route would have on I-35 in terms of traffic, maintenance, and commerce.

The Trans-Texas Corridor was first proposed by TexasGovernorRick Perry in 2002. It consisted of a 1,200 foot (366 m) wide highway that also carried utilities such as electricity, petroleum and water as well as railway track and fiber-optic cables.[14] In July 2007, U.S. Representative Duncan Hunter successfully offered an amendment to House Resolution 3074, the FY2008 Transportation Appropriations Act, prohibiting the use of federal funds for Department of Transportation participation in the activities of the Security and Prosperity Partnership of North America (SPP). Hunter stated that: "Unfortunately, very little is known about the NAFTA Super Highway. This amendment will provide Congress the opportunity to exercise oversight of the highway, which remains a subject of question and uncertainty, and ensure that our safety and security will not be compromised in order to promote the business interests of our neighbors."[15] Fellow Republican Congressman and presidential candidate Ron Paul brought the issue to mainstream prominence during the December 2007 CNN-YouTube GOP debate, where he rejected the concept and also called it the NAFTA Superhighway after the North American Free Trade Agreement and, like Hunter, framed it within the ultimate goal of creating a North American Union.

In 2011, the Texas Legislature formally repealed its authority for the establishment and operation
of the Trans-Texas Corridor, with the passage of HB 1201.[16][17]